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U.S. Department of Health and Human Services

About FDA

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Office of Pharmaceutical Science - Science Initiatives

Electronic Regulatory Submissions and Review (ERSR)

Since January 1999, sponsors have been able to submit New Drug Applications (NDAs), and amendments and supplements to NDAs, in electronic form in lieu of paper. Acceptable formats are Adobe's Portable Document Format (PDF) for "electronic paper," that is, the narrative, tables, and graphics making up the submission; and SAS Transport for data sets. Sponsors may submit SAS Transport data sets in lieu of voluminous Case Report Tabulations, a benefit both to sponsors and to the agency. During 1999, the Center for Drug Evaluation and Research (CDER) received 250 electronic NDA submissions from 58 different companies. 

OPS is working with other CDER components on the development of draft guidances which will reflect this more comprehensive and integrated ERSR strategy. These will include guidances on ANDA, IND, Annual Reports, and DMF submissions, as well as refinements of the current guidance on NDA submissions.

Chemistry, Manufacturing, and Control (CMC) Risk-Based Review Proposal

This proposal aims to carve out a list of drugs with little or low risk to focus more time on complex drugs which can have problems with product quality. The objective is to come up with a list of quality attributes and acceptance criteria for little or no risk drugs. This will result in guidance to industry with reduced information being submitted for review. An ANDA can be considered a CMC supplement where everything from manufacturing, suppliers, manufacturing sites is changed. If a drug meets the list then the original NDA could be considered a truncated ANDA with information just like the annual report of the existing approved NDA.

Biopharmaceutic Classification System (BCS)

The BCS is a scientific framework for classifying drug substances based on their aqueous solubility and intestinal permeability. When combined with dissolution of the drug product, the BCS takes into account three major factors that govern the rate and extent of drug absorption from immediate release solid oral dosage forms: solubility, permeability and dissolution.

Regulatory Impact of BCS:

  • INDs/NDAs:  waiver of bioequivalence (BE) studies following changes to components, composition, and/or method of manufacture.
  • ANDAs:  test and reference products must be highly soluble, highly permeable and rapidly dissolving.
  • Postapproval:  biowaivers for significant postapproval changes.

For additional information visit the BCS web page.

St. John's Wort/Drug-Drug Interactions

Drug-drug interactions are an important component of an NDA evaluation, as well as post-marketing surveillance. Many drug-drug interactions result from cytochrome P-450 interactions (CYP 450), which may result in toxic overexposure to one or more types of drugs, or underexposure to a given drug resulting in suboptimal therapy. Recent advances in this area of drug metabolism have lead to in vitro CYP 450 screening that allows pre-clinical determinations of potential in vivo drug-drug interactions.

However, drug-drug interactions are occasionally observed with drugs as well as foods and dietary supplements that were not screened in this fashion. One current example is St. John's Wort, an herbal preparation, that has become the focus of considerable attention because of its interaction with indinavir, an antiretroviral drug, which has lead to sub-optimal concentrations and a loss of virologic response. In addition to this interaction, St. John's Wort has been implicated in drug-drug interactions with approximately ten drugs. These interactions are of great interest clinically because these interactions have occurred for widely used medications that possess significant side-effects. In addition, these interactions are scientifically interesting because they are characterized by more than one mechanism (enzyme induction as well as enzyme inhibition) and more than one CYP 450 isozyme may be involved. Until these interactions have been fully elucidated and more data becomes available, the FDA has issued letters to health care providers and patients warning against the use of St. John's Wort in combination with certain prescription drugs (e.g. AIDS therapy).